Genetic studies have been a major tool fueling the tremendous growth in PD research over the last 10 years. Project 1 builds on our very successful work, 50 publicafions, 60 abstracts over the last funding period, examining the effect of common variants (CV) (polymorphisms) in PD. Table 1 shows the three primary types of genetic variafions that contribute to disease risk. Genome wide association studies (GWAS) have focused on exploring the contribufion of CV to disease suscepfibility. While the tradifional definifion of CV is a minor allele frequency (MAF) >1% in the populafion, in pracfice, GWAS and associafion studies have only looked at CV with a MAF>5%. So we have defined CV for this proposal as those variants with MAF>5%. The individual contribution to disease risk (odds ratios) per CV is small. Therefore, it is the accumulation of CV associated with PD that affects the overall risk for PD in an individual. One of the first descriptions of rare variants (RV) came from (1) who suggested that "subfie or unconvenfional mutafions in cancer predisposifion genes" may contribute to the increased risk of cancer observed in family members of cancer patients. Cohen et al (2) suggested that "variants are likely to be rare individually;they may be sufficiently common in aggregate (in a gene) to contribute to variafion in common traits in the populafion". RV can be considered genetic variations that often present with mildly deleterious effects on protein function. Their effect on gene and protein function is thought to lie between that of CV and those severely deleterious mutations (M). Recent estimates (3) suggest that 53% of de novo missense mutations fall within this RV category. This would be high enough to ensure their confinued presence in the population, and would support their presence as a significant explanafion for the genefic contribufions of common disease. Indeed, Bodmer and Bonilla (4) in a recent review of RV suggest that 1/3 of the population attributable risk for complex disease may come from RV. Indeed, several examples of RV are already known in PD (5,6). Mutafions are the rarest of DNA changes, and functionally cause PD tjy themselves. These are the changes that we refer to as Mendelian (autosomal recessive, autosomal dominant, or X-linked). Mutafions are well known in PD as well (7). Identifying CV for association has been very successful. Six GWAS studies have now been reported for PD. However, only SNCA and MAPT have had highly significant associafion with PD across all of the studies. (8-13). Therefore, there is increasing realization that CV alone are not responsible for the genetic contribution to risk for PD and many other complex disorders. (14-17). This strongly suggests that the other categories of DNA variafion in Table 1 must have a substantial contribution to PD. As RV can only be seen by sequencing (Table 1) it is only with the availability of an established target enrichment technology, that captures specific DNA sequences for "next-generation" sequencers (NGS), that we can search for RV/M on a large scale. Large versions of this same approach have lead to whole exome sequencing, i.e. providing sequence on 180,000 exons in each individual (18-20). We will use both of these approaches in this project. The resulting sequence data and RV/M from this project will be used by both Projects 1 and 2. For cost and efficiency, we have included the 70 mitochondrial genes of project 2 in the inifial sequencing of project 1. However, follow-up on these genes will occur in project 2. In addifion, genes identified bv proiect 3 will be incorporated in subsequent DNA captures of project 1. The project will be administrated by Core A. and all individuals for sequencing will be obtained from Core B. The considerable stafisfical and bioinformafic analyses will be done in conjunction with Core C. Laboratory opportunlfies for Neurology residents and clinical experience for Project 1 laboratory personnel will be given through Cores B and D.